Primary open-angle glaucoma (POAG) is an age-related, intraocular pressure (lOP)-dependent progressive optic neuropathy that ultimately leads to blindness. Permanent vision loss from POAG is a condition of public health significance. Current evidence suggests that POAG is a polygenetic disease modified by environmental influences. We hypothesize that the identification and characterization of POAG susceptibility genes via a genome-wide association study (GWAS) will reveal significant environmental determinants that influence the disease process, as well as a better understanding of how gene-environment and gene-gene interactions contribute to this complex disease. For this study we have formulated a case-control study population from three cohorts: the Nurses Health Study (NHS);Health Professionals Follow-up Study (HPFS);and Massachusetts Eye and Ear Infirmary (MEEI). The cohort consists of 1200 cases and 1200 controls with DMA. Members of the NHS and HPFS also have repeated environmental exposure data over a 16 to 24 year period. We will perform a single-stage GWAS and carry out the appropriate statistical analyses to find genetic markers with the strongest association with POAG. Our replication plan to confirm the top genetic markers will involve a comparable population of 1400 cases and 1400 controls, a significant subset of which will also have repeated environmental exposure data. As part of this study, we will submit data on a myriad of environmental exposures (from members of NHS and HPFS) that could modify genetic predisposition for POAG to a central data repository. These results will generate a valuable collection of genotype, phenotype and environment exposure data, allowing scientists to test numerous hypotheses regarding how genes and environment relate to incident POAG. This study is also a crucial first step toward a better understanding of the underlying pathology responsible for POAG and will lead to future proposals to examine the relevance of the significant variants found in the Caucasian population in an African American admixture study, perform fine mapping and re-sequencing of candidate genes in at-risk populations, and investigate gene-gene interactions in POAG. Discovery of the various combinations of gene and environment interactions involved in POAG could lead to genotype-specific primary prevention strategies for this disease.